To the Editor: The paper by Yasui et al. 1 showing elevated plasma homocysteine levels in levodopa-treated patients with PD is interesting and confirms other reports2 and our unpublished findings (table). It also shows that patients with the TT-genotype of the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) have especially high homocysteine levels. These findings have to be related to the metabolism of levodopa and methyl groups and may have importance in the future treatment of PD with levodopa.

Homocysteine is the demethylated derivative of methionine and is only formed in numerous transmethylation reactions (eg, catecholamine O-methyltransferase [COMT]) that use S-adenosylmethionine (SAM) as the methyl donor. 3 Most administered levodopa is COMT-methylated to 3O-methyldopa and the methylation of 1000 mg of levodopa consumes 5 mMol of SAM methyls and produces 5 mMol of S-adenosylhomocysteine (SAH), which then is deadenosylated to homocysteine. In the study of Yasui et al., the average levodopa dose was 1500 mg. Therefore, it is most likely that levodopa treatment contributed to hyperhomocysteinemia in their patients with PD. In this context it is important to note that humans normally consume about 15 mMol/day of SAM methyls for methylation of endogenous compounds such as phospholipids, DNA, myeline, and proteins. About 10 mMol of these methyls are supplied from food, mainly as methionine and choline, and about 5 mMol are de novo synthesized in one-carbon (folate) metabolism and are transferred by a vitamin B12-dependent reaction to homocysteine, again forming methionine and SAM. 4